Trastuzumab Emtansine (T-DM1): Hitching a Ride on a Therapeutic Antibody

2012 ◽  
pp. 159-161 ◽  
Author(s):  
Howard A. Burris
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Side Effects ◽  
Phase Ii ◽  
Objective Response ◽  
Metastatic Breast ◽  
Response Rates ◽  
Phase Iii ◽  
Trastuzumab Emtansine ◽  
Her2 Positive

Overview: The treatment of cancers with chemotherapy is frequently limited by side effects. The effectiveness may be improved by the use of monoclonal antibodies to deliver cytotoxic agents to cancer cells while limiting exposure to normal tissues. The use of antibody-drug conjugates (ADCs) is one such strategy: a drug connected by a linker to an antibody specific for a tumor antigen is the basic makeup of an ADC. Overexpression and amplification of HER2 is associated with clinically aggressive breast cancers, and the use of trastuzumab to target HER2 has been highly effective. That said, most patients with HER2-positive metastatic breast cancer will eventually have disease progression during targeted therapy. Trastuzumab emtansine (T–DM1) is a novel ADC that combines the humanized antibody trastuzumab and the potent antimicrotubule agent T-DM1 (derivative of maytansine) using a unique and highly stable linker. The potential of maytansine was found in the 1970s with clinical responses noted against breast cancer; however, substantial toxicity prohibited further development. DM1 possesses in vitro cytotoxicity 10 to 200 times greater than that of taxanes and vinca alkaloids. A phase I trial of T-DM1 for patients with heavily pretreated HER2-positive breast cancer determined a recommended dose of 3.6 mg per kilogram delivered every 3 weeks. Responses were seen in multiple patients. T-DM1 was then studied in phase II trials of patients with HER2-positive metastatic breast cancer. In a studies of 112 and 110 patients in whom disease had progressed during HER2-directed therapy, T-DM1 was associated with objective response rates of 26% and 34%, respectively. The agent was well tolerated in both trials, with most toxicities being grade 1 and 2, and no bleeding episodes or cardiac events occurring. Additional phase II and III trials are now evaluating T-DM1 in the first-line setting. In one such trial, T-DM1 was compared with standard dosing of trastuzumab every 3 weeks plus docetaxel every 3 weeks. Objective response rates were comparable and grade 3 or4 adverse events were substantially reduced in the T-DM1 arm. The anticipated selective activity and reduction in side effects were thus noted. Randomized multicenter phase III trials are ongoing, including the EMILIA trial, an open-label trial of T-DM1 compared with the U.S. Food & Drug Administration-approved regimen of capecitabine plus lapatinib. The results of studies completed to date suggest T-DM1 is active in patients who have cancer resistant to trastuzumab-based combinations.

Pyrotinib plus capecitabine for HER2-positive metastatic breast cancer patients with brain metastases (PERMEATE): A multicenter, single-arm phase II study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 1037-1037
Author(s):  
Min Yan ◽  
Quchang Ouyang ◽  
Tao Sun ◽  
Limin Niu ◽  
Jin Yang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Brain Metastases ◽  
Phase Ii ◽  
Kinase Inhibitor ◽  
Objective Response ◽  
Metastatic Breast ◽  
Phase Iii ◽  
Breast Cancer Patients ◽  
Her2 Positive

1037 Background: HER2-positive metastatic breast cancer (BC) has a high risk of brain metastases (BM), leading to poor survival. Small molecule tyrosine kinase inhibitor (TKI) with enhanced penetrability to the blood brain barrier combined with capecitabine have demonstrated promising clinical outcomes in HER2-positive metastatic BC patients with untreated (such as lapatinib) or previously treated (such as neratinib) BM. The randomized phase III PHOEBE trial has proved better efficacy of pyrotinib, an irreversible pan-HER receptor TKI, versus lapatinib when in combination with capecitabine in HER2-positive local relapsed or metastatic BC. This study was conducted to investigate the efficacy and safety of pyrotinib plus capecitabine in HER2-positive metastatic BC patients with BM. Methods: In this multicenter phase II trial (NCT03691051), eligible patients received pyrotinib 400 mg orally once daily without breaks and capecitabine 1000 mg/m2 orally twice daily for 14 days followed by 7 days off. Treatment was continued until disease progression or intolerable toxicity. Prior HER2 TKIs were not allowed. Cohort A included patients with radiotherapy-naive BM, and cohort B included those with progressive BM after whole brain radiotherapy or stereotactic conformal radiotherapy. The primary endpoint was confirmed central nervous system (CNS) objective response rate (ORR), as assessed according to the Response Evaluation Criteria In Solid Tumors version 1.1. Results: Between January 2018 and July 2020, a total of 78 female patients were included (Table). For cohort A (n = 59), the CNS ORR was 74.6% (95%CI: 61.6%-85.0%). For cohort B (n = 19), the CNS ORR was 42.1% (95%CI: 20.3%-66.5%). By the cutoff date on 25 January 2021, the median progression-free survival was 12.1 months (95%CI: 9.0-14.7) in cohort A and 5.6 months (95%CI: 3.4-10.7) in cohort B. The most common grade ≥3 adverse events were diarrhea (23.1% [18/78]), neutrophil count decreased (12.8% [10/78]), white blood cell count decreased (12.8% [10/78]), anemia (9.0% [7/78]), hand-foot syndrome (7.7% [6/78]), hypertriglyceridemia (6.4% [5/78]), and hypokalemia (5.1% [4/78]). Conclusions: Pyrotinib plus capecitabine resulted as an effective and safe treatment for HER2-positive BC patients with radiotherapy-naive BM, but the efficacy was modest in those with radiotherapy-treated BM. Clinical trial information: NCT03691051 .[Table: see text]

scholarly journals Neratinib Plus Capecitabine Versus Lapatinib Plus Capecitabine in HER2-Positive Metastatic Breast Cancer Previously Treated With ≥ 2 HER2-Directed Regimens: Phase III NALA Trial

2020 ◽  
Vol 38 (27) ◽  
pp. 3138-3149 ◽  
Author(s):  
Cristina Saura ◽  
Mafalda Oliveira ◽  
Yin-Hsun Feng ◽  
Ming-Shen Dai ◽  
Shang-Wen Chen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Kinase Inhibitor ◽  
Objective Response ◽  
Metastatic Breast ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Her2 Positive ◽  
End Points ◽  
Cns Disease

PURPOSE NALA (ClinicalTrials.gov identifier: NCT01808573 ) is a randomized, active-controlled, phase III trial comparing neratinib, an irreversible pan-HER tyrosine kinase inhibitor (TKI), plus capecitabine (N+C) against lapatinib, a reversible dual TKI, plus capecitabine (L+C) in patients with centrally confirmed HER2-positive, metastatic breast cancer (MBC) with ≥ 2 previous HER2-directed MBC regimens. METHODS Patients, including those with stable, asymptomatic CNS disease, were randomly assigned 1:1 to neratinib (240 mg once every day) plus capecitabine (750 mg/m2 twice a day 14 d/21 d) with loperamide prophylaxis, or to lapatinib (1,250 mg once every day) plus capecitabine (1,000 mg/m2 twice a day 14 d/21 d). Coprimary end points were centrally confirmed progression-free survival (PFS) and overall survival (OS). NALA was considered positive if either primary end point was met (α split between end points). Secondary end points were time to CNS disease intervention, investigator-assessed PFS, objective response rate (ORR), duration of response (DoR), clinical benefit rate, safety, and health-related quality of life (HRQoL). RESULTS A total of 621 patients from 28 countries were randomly assigned (N+C, n = 307; L+C, n = 314). Centrally reviewed PFS was improved with N+C (hazard ratio [HR], 0.76; 95% CI, 0.63 to 0.93; stratified log-rank P = .0059). The OS HR was 0.88 (95% CI, 0.72 to 1.07; P = .2098). Fewer interventions for CNS disease occurred with N+C versus L+C (cumulative incidence, 22.8% v 29.2%; P = .043). ORRs were N+C 32.8% (95% CI, 27.1 to 38.9) and L+C 26.7% (95% CI, 21.5 to 32.4; P = .1201); median DoR was 8.5 versus 5.6 months, respectively (HR, 0.50; 95% CI, 0.33 to 0.74; P = .0004). The most common all-grade adverse events were diarrhea (N+C 83% v L+C 66%) and nausea (53% v 42%). Discontinuation rates and HRQoL were similar between groups. CONCLUSION N+C significantly improved PFS and time to intervention for CNS disease versus L+C. No new N+C safety signals were observed.

Phase II multicenter study of talazoparib for somatic BRCA1/2 mutant metastatic breast cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS1110-TPS1110
Author(s):  
Neelima Vidula ◽  
Erica Blouch ◽  
Nora K. Horick ◽  
Erin Basile ◽  
Senthil Damodaran ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Trial ◽  
Metastatic Breast Cancer ◽  
Phase Ii ◽  
Parp Inhibitor ◽  
Objective Response ◽  
Metastatic Breast ◽  
Parp Inhibitors ◽  
Phase Iii ◽  
Patient Reported

TPS1110 Background: PARP inhibitors are approved for the treatment of HER2 negative metastatic breast cancer (MBC) with germline BRCA1/2 mutations, based on phase III studies demonstrating an improvement in progression-free survival (PFS) compared to chemotherapy in this population and better patient reported outcomes (Robson, NEJM, 2017; Litton, NEJM, 2018). However, germline BRCA1/2 mutations account for only 5-10% of breast cancer, limiting the current clinical applicability of PARP inhibitors. Somatic BRCA1/2 mutations are detectable in circulating cell-free DNA (cfDNA) in ̃13.5% of patients with MBC; in pre-clinical models, pathogenic somatic BRCA1/2 mutations have been shown to respond to PARP inhibition (Vidula, CCR, 2020). The purpose of this study is to evaluate the efficacy of talazoparib, a PARP inhibitor, in patients with MBC who have somatic BRCA1/2 mutations detectable in cfDNA, in the absence of a germline BRCA1/2 mutation, which we hypothesize will be effective in this setting. This study may help expand the population of patients with MBC who benefit from PARP inhibitors. Methods: This is an investigator initiated multicenter, single arm, phase II clinical trial studying the efficacy of talazoparib in 30 patients with MBC who have pathogenic somatic BRCA1/2 mutations detected in cfDNA. Patients with MBC who are found to have pathogenic somatic BRCA1/2 mutations detected in cfDNA in the absence of a germline BRCA1/2 mutation are eligible. Patients may have triple negative (with ≥ 1 prior chemotherapy), or hormone receptor positive/HER2 negative breast cancer (with ≥ 1 prior hormone therapy). Patients may have received any number of prior lines of chemotherapy, including a prior platinum (in the absence of progression). They must have adequate organ function and ECOG performance status ≤2, and should not have previously received a PARP inhibitor. Patients are treated with talazoparib 1 mg daily until disease progression or intolerability, with serial imaging using CT chest/abdomen/pelvis and bone scan performed at baseline and every 12 weeks, and cfDNA collection every 4 weeks. Primary endpoint is PFS by RECIST 1.1. Patients are being enrolled in a two-stage design with 80% power to demonstrate that the treatment is associated with “success” (PFS > 12 weeks) in ≥53% patients (4% alpha). Secondary endpoints include objective response rate and safety (NCI CTCAE v 5.0). Exploratory analyses include studying serial changes in cfDNA BRCA1/2 mutant allelic frequency and comparing pre-and post-treatment cfDNA for the emergence of BRCA1/2 reversion and resistance mutations. This study is activated and open at Massachusetts General Hospital, where 2 patients are completing screening. It is also opening soon at 6 other academic centers (NCT03990896). Grant support includes a Pfizer ASPIRE award and 2020 Conquer Cancer Foundation of ASCO – Breast Cancer Research Foundation – Career Development Award. Clinical trial information: NCT03990896 .

Vinflunine in combination with trastuzumab for treatment of HER2-positive metastatic breast cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 1058-1058 ◽  
Author(s):  
R. Paridaens ◽  
H. Wildiers ◽  
F. Dalenc ◽  
O. Rixe ◽  
V. Cadic ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Confidence Interval ◽  
Antitumour Activity ◽  
Vinca Alkaloid ◽  
Metastatic Breast ◽  
Response Rates ◽  
Phase Iii ◽  
Second Line ◽  
Her2 Positive

1058 Background: Vinflunine (VFL) is a microtubule inhibitor of the vinca alkaloid class with high activity in several tumour types especially in second line treatment of metastatic breast cancer (MBC). Over-expression of HER2 is observed in 20–25% of all breast cancers and is associated with a poor prognosis. The development of the anti-HER2 therapy with trastuzumab (T) allowed significant prolonging of the survival in HER2 positive MBC. The combination of these two compounds which are separately active in MBC warranted a combination study. Methods: This phase I was designed to determine the recommended dose (RD) of VFL in combination with T for treatment of first or second line MBC patients (pts), to assess its safety profile, and to determine its antitumour activity. Results: Thirty pts, median age 55 [33–74] years, WHO performance status 0/1: 18/12 pts , respectively were given VFL 280 mg/m2 (10 pts) or 320 mg/m2 (20 pts) day 1 every 3 weeks (w) in combination with T (loading dose 4 mg/kg and subsequently 2 mg/kg/w). Six pts were chemonaive and 5 pts received this combination in second line. At the first VFL dose (280 mg/m2), 0/6 pts experienced dose-limiting toxicity. The RD was established at 320 mg/m2 in the following 6 pts. All 30 pts are evaluable for safety. Haematological toxicities were: anaemia grade (G) 3: 0 and 1 pt; neutropenia G 3/4: 5/17 pts, febrile neutropenia 0/2 pts with VFL 280 and 320 mg/m2, respectively. G 3 non-haematological adverse events were only reported in the 20 pts receiving VFL 320 mg/m2: fatigue and myalgia: 5 pts; constipation: 4 pts; abdominal pain, neutropenic infection: 2 pts. ileus, hyponatremia, arthralgia: 1 pt. No significant cardiac events were observed. The response rates, 62.5% [95% confidence interval: 24.5–91.5] and 73.7% [95% confidence interval: 48.8–90.9] in pts receiving VFL at 280 mg/m2 and 320 mg/m2 respectively, were established by an external radiologist using RECIST in the first 27 evaluable patients. Conclusions: Vinflunine/trastuzumab combination is feasible with encouraging response rates and manageable toxicity in MBC pts. A phase III study comparing VFL + T versus paclitaxel + T has been initiated. No significant financial relationships to disclose.

Trastuzumab emtansine (T-DM1) and ribociclib, an oral inhibitor of cyclin dependent kinase 4 and 6 (CDK 4/6), for patients with metastatic HER2-positive breast cancer: Phase 1b clinical trial.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS1106-TPS1106 ◽  
Author(s):  
Laura Spring ◽  
Shom Goel ◽  
Dejan Juric ◽  
Steven J. Isakoff ◽  
Stephanie Haddad ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Trial ◽  
Metastatic Breast Cancer ◽  
Objective Response ◽  
Metastatic Breast ◽  
Clinical Activity ◽  
Trastuzumab Emtansine ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Positive Breast Cancer

TPS1106 Background: Despite the availability of multiple effective therapies, most patients with metastatic HER2-positive breast cancer will experience disease progression and death. While traditionally the focus has been targeting the HER receptor family itself, combinations involving targets downstream of the HER2 pathway, particularly CDK 4/6, could potentially enhance therapeutic efficacy. In pre-clinical models of acquired resistance to HER2-targeted therapies, inhibition of CDK4/6 has been shown to result in tumor inhibition. Trial Design: This phase Ib, single arm, open-label clinical trialis investigating the combination of Trastuzumab emtansine (T-DM1) and the CDK4/6 inhibitor, ribociclib (LEE011). Eligible patients include patients age ≥ 18 years with HER2-positive metastatic breast cancer. Prior treatment with at least one regimen containing trastuzumab and a taxane is required. Ribociclib is given orally for two weeks of a 21-day cycle (days 8-21), with T-DM1 given at standard dose every 3 weeks on day 1. Trial Objectives: 1. To estimate the MTD and/or RP2D of ribociclib in combination with T-DM1. 2. To assess the safety and tolerability of ribociclib in combination with T-DM1. 3. To explore the clinical activity of T-DM1 and ribociclib in HER2-positive metastatic breast cancer. 4. To assess potential biomarkers of response to ribociclib in combination with T-DM1. Statistical Methods: A standard 3+3 dose escalation design is being used to evaluate various doses of ribociclib in combination with T-DM1 to determine the maximum tolerated dose (MTD) and/or recommended phase-2 dose (RP2D). Once MTD/RP2D is determined there will be a dose-expansion cohort (N = l5) to confirm the safety profile and evaluate preliminary evidence of efficacy, including objective response rate (ORR) by RECIST 1.1 and progression-free survival (PFS). Clinical trial information: NCT02657343.

Pyrotinib plus capecitabine for HER2-positive, trastuzumab-resistant metastatic breast cancer: A pooled analysis of three randomized controlled trials.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 1048-1048
Author(s):  
Zefei Jiang ◽  
Binghe Xu ◽  
Min Yan ◽  
Quchang Ouyang ◽  
Xi-Chun Hu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Randomized Controlled Trials ◽  
Objective Response ◽  
Metastatic Breast ◽  
Pooled Analysis ◽  
Phase Iii ◽  
Controlled Trials ◽  
Her2 Positive ◽  
Randomized Controlled

1048 Background: Trastuzumab is the most widely used anti-HER2 agent in patients (pts) with HER2-positive breast cancer, both in (neo)adjuvant and metastatic settings; however, drug resistance is inevitable. This pooled study aimed to investigate the efficacy of pyrotinib plus capecitabine in pts with HER2-positive, trastuzumab-resistant relapsed or metastatic breast cancer. Methods: Data were derived from three randomized controlled trials, including a phase II (NCT02422199) and the PHOEBE phase III (NCT03080805) study comparing pyrotinib plus capecitabine vs lapatinib plus capecitabine and the PHENIX phase III (NCT02973737) study comparing pyrotinib plus capecitabine vs placebo plus capecitabine. Pts with trastuzumab-resistant disease were included in the analyses, including 39 pts who had relapsed within six months after adjuvant trastuzumab and 57 pts who had progressed within three months of trastuzumab treatment for metastatic disease. The pooled tumor response data (per blinded independent central review) were reported herein. Results: In the pooled analysis of all three studies, 63 pts received pyrotinib plus capecitabine. Among them, 28 (44.4%) pts had disease progression or died. The median progression free survival (PFS) was 12.4 months (95% CI, 6.9 to not reached). In total, 40 pts (63.5% [95% CI, 50.4% to 75.3%]) achieved objective response, and the estimated median duration of response (DoR) was 11.1 months (95% CI, 6.9 to not reached). In the pooled analysis involving the phase II and PHOEBE phase III, 43 pts were treated with pyrotinib plus capecitabine and 33 pts with lapatinib plus capecitabine. In total, 18 (41.9%) pts with pyrotinib plus capecitabine and 17 (51.5%) pts with lapatinib plus capecitabine had disease progression or died. The PFS tended to be prolonged with pyrotinib plus capecitabine vs lapatinib plus capecitabine (median, 12.4 months [95% CI, 6.9 to not reached] vs 6.9 months [95% CI, 5.5 to not reached]; hazard ratio, 0.62 [95% CI, 0.31 to 1.24]; p=0.0864). The objective response rate was 67.4% (95% CI, 51.5% to 80.9%) with pyrotinib plus capecitabine compared with 54.5% (95% CI, 36.4% to 71.9%) with lapatinib plus capecitabine. The estimated median DoR was 11.1 months [95% CI, 6.9 to not reached] vs not reached [95% CI, 4.2 months to not reached], respectively. Conclusions: Pyrotinib plus capecitabine showed favorable efficacy in pts with HER2-positive, trastuzumab-resistant relapsed or metastatic breast cancer. This combination could be a treatment option for this population.

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